Alfin G. Vicencio

TGF-β signaling is dynamically regulated during the alveolarization of rodent and human lungs

Although transforming growth factor‐beta (TGF‐β) signaling negatively regulates branching morphogenesis in early lung development, few studies to date have addressed the role of this family of growth factors during late lung development. We describe here that the expression, tissue localization, and activity of components of the TGF‐β signaling machinery are dynamically regulated during late lung development in the mouse and human. Pronounced changes in the expression and localization of the TGF‐β receptors Acvrl1, Tgfbr1, Tgfbr2, Tgfbr3, and endoglin, and the intracellular messengers Smad2, Smad3, Smad4, Smad6, and Smad7 were noted as mouse and human lungs progressed through the canalicular, saccular, and alveolar stages of development. TGF‐β signaling, assessed by phosphorylation of Smad2, was detected in the vascular and airway smooth muscle, as well as the alveolar and airway epithelium throughout late lung development. These data suggest that active TGF‐β signaling is required for normal late lung development. Developmental Dynamics 237:259–269, 2008.

Severe Asthma With Fungal Sensitization in a Child: Response to Itraconazole Therapy

People with severe asthma with fungal sensitization may represent an underdiagnosed subset of patients with refractory disease. It is important to know that such patients may benefit from adjunct treatment with antifungal agents. We describe here the case of a child with refractory asthma, persistent airway obstruction, a serum immunoglobulin E level of >20000 IU/mL, and severe eosinophilic airway infiltration. Although he did not meet diagnostic criteria for allergic bronchopulmonary aspergillosis, he demonstrated evidence of sensitization to several fungi and responded dramatically to the addition of itraconazole therapy. We also discuss emerging hypotheses regarding fungal-induced asthma.

Fungal sensitization in childhood persistent asthma is associated with disease severity.

Recent observations, especially in adults, suggest that asthma severity may be associated with fungal sensitization. Other studies suggest that some patients with severe asthma and fungal sensitization may benefit from anti‐fungal therapy. Currently, the prevalence of fungal sensitization among children with severe asthma is not well characterized.

Infectious Chlamydia pneumoniae is associated with elevated interleukin-8 and airway neutrophilia in children with refractory asthma

Background: Neutrophilic asthma is thought to be less responsive than eosinophilic asthma to anti-inflammatory therapies including corticosteroids. Chlamydia pneumoniae has been implicated in asthma, possibly by induction of interleukin (IL-8). We hypothesized that IL-8 is increased in the bronchoalveolar lavage (BAL) fluid from children with asthma and C. pneumoniae. Methods: BAL fluid was analyzed for C. pneumoniae and IL-8 using polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay from 2 asthma patient populations in the Bronx, NY and Massachusetts with an average age of 8 and 8.7 years old, respectively. For comparison, samples were also analyzed for C. trachomatis and Mycoplasma 16s DNA. Results: Of 18 Bronx samples analyzed, 6 (33%) were PCR-positive for C. pneumoniae, 10 (56%) for C. trachomatis, and 8 (44%) for Mycoplasma 16s DNA. IL-8 from C. pneumoniae-positive samples was 3.3-fold higher compared with negative samples (P = 0.003). There was no difference between patients tested for C. trachomatis or Mycoplasma. Of 84 Massachusetts samples analyzed, 42 (50%) were PCR-positive for C. pneumoniae, 42 (50%) for C. trachomatis, and 13 (16%) for Mycoplasma. IL-8 concentration from C. pneumoniae-positive samples was 10.49-fold higher compared with negative samples (P = 0.0001). As in the Bronx cohort, there were no differences between patients tested for C. trachomatis or Mycoplasma. Lastly, BAL neutrophilia predicted the presence of C. pneumoniae but not Mycoplasma or C. trachomatis. Conclusions: Children with asthma who were PCR-positive for C. pneumoniae demonstrated elevated concentrations of IL-8 and neutrophils in BAL fluid compared with similar patients who were positive for C. trachomatis or Mycoplasma organisms, but PCR-negative for C. pneumoniae. Undiagnosed C. pneumoniae infection in children may therefore contribute to poorly controlled asthma via induction of IL-8.

Pulmonary cryptococcosis induces chitinase in the rat

BackgroundWe previously demonstrated that chronic pulmonary infection with Cryptococcus neoformans results in enhanced allergic inflammation and airway hyperreactivity in a rat model. Because the cell wall of C. neoformans consists of chitin, and since acidic mammalian chitinase (AMCase) has recently been implicated as a novel mediator of asthma, we sought to determine whether such infection induces chitinase activity and expression of AMCase in the rat.MethodsWe utilized a previously-established model of chronic C. neoformans pulmonary infection in the rat to analyze the activity, expression and localization of AMCase.ResultsOur studies indicate that intratracheal inoculation of C. neoformans induces chitinase activity within the lung and bronchoalveolar lavage fluid of infected rats. Chitinase activity is also elicited by pulmonary infection with other fungi (e.g. C. albicans), but not by the inoculation of dead organisms. Enhanced chitinase activity reflects increased AMCase expression by airway epithelial cells and alveolar macrophages. Systemic cryptococcosis is not associated with increased pulmonary chitinase activity or AMCase expression.ConclusionOur findings indicate a possible link between respiratory fungal infections, including C. neoformans, and asthma through the induction of AMCase.

Increased chitinase expression and fungal-specific antibodies in the bronchoalveolar lavage fluid of asthmatic children.

Increasing evidence highlights the contribution of chitinases and fungal infection to the development of asthma.

The Chitin Connection

ABSTRACT Chitin, a polymer of N-acetylglucosamine, is an essential component of the fungal cell wall. Chitosan, a deacetylated form of chitin, is also important in maintaining cell wall integrity and is essential for Cryptococcus neoformans virulence. In their article, Gilbert et al. [N. M. Gilbert, L. G. Baker, C. A. Specht, and J. K. Lodge, mBio 3(1):e00007-12, 2012] demonstrate that the enzyme responsible for chitosan synthesis, chitin deacetylase (CDA), is differentially attached to the cell membrane and wall. Bioactivity is localized to the cell membrane, where it is covalently linked via a glycosylphosphatidylinositol (GPI) anchor. Findings from this study significantly enhance our understanding of cryptococcal cell wall biology. Besides the role of chitin in supporting structural stability, chitin and host enzymes with chitinase activity have an important role in host defense and modifying the inflammatory response. Thus, chitin appears to provide a link between the fungus and host that involves both innate and adaptive immune responses. Recently, there has been increased attention to the role of chitinases in the pathogenesis of allergic inflammation, especially asthma. We review these findings and explore the possible connection between fungal infections, the induction of chitinases, and asthma.

CHIT1 Mutations: Genetic Risk Factor for Severe Asthma With Fungal Sensitization?

Fungi can exacerbate symptoms in patients with asthma. To our knowledge, genetic risk factors for fungal-associated asthma have not been described. We present here the cases of 6 children who carried the diagnosis of severe asthma with fungal sensitization, 3 of whom were treated with and responded clinically to itraconazole therapy. All 6 patients were heterozygous for a 24-base pair duplication in the CHIT1 gene, which has been associated with decreased levels of circulating chitotriosidase and susceptibility to fungal infection.

Pulmonary atelectasis in children anesthetized for cardiothoracic MR: Evaluation of risk factors

Purpose: To systematically assess the frequency and risk factors for atelectasis in children anesthetized for cardiothoracic magnetic resonance (MR). Materials and Methods We retrospectively identified 58 consecutive children (age range, 6 days to 21 years) who underwent cardiothoracic MR from January 2001 to December 2004 whose imaging and medical charts were available. One certificate of added qualification pediatric radiologist and 1 of 2 cardiothoracic radiologists, in consensus, evaluated the first and last set of axial images. Images were evaluated for cardiac, vascular and tracheobronchial abnormalities, and degree of atelectasis. Atelectasis was considered significant if the equivalent of 3 or more segments were involved. Patients received 1 or more of 7 anesthetic medications (n = 27), chloral hydrate alone (n = 4), or required no anesthesia (n = 27). Results: Significant atelectasis developed only in those receiving anesthetic medications. Thirty-seven percent (10/27) of anesthetized children developed significant atelectasis in the first and/or last axial sequence. In 90% (9 /10) of patients, it developed in the first axial sequence. Strong risk factors were age younger than 1 year (80%, 8/10, P = 0.029) and MR evidence of tracheobronchial narrowing (50%, 5/10, P = 0.008). In patients with vascular ring, there was a trend toward significance (40%, 4/10, P = 0.09). None of the anesthesia factors were significant, including ventilation mode, anesthesia duration, or American Society of Anesthesiology risk (all P > 0.1). Conclusions: Atelectasis may occur shortly after induction of anesthesia in children younger than 1 year of age or with tracheobronchial narrowing when anesthetized for cardiothoracic MR.

Flexible bronchoscopy and interdisciplinary collaboration in pediatric large airway disease

OBJECTIVE Demonstrate the benefits of a multidisciplinary pediatric airway team prepared to evaluate and treat otolaryngology patients with flexible bronchoscopy. DESIGN Case series. SETTING Tertiary, academic childrens hospital. PATIENTS 10 children (5 male, 5 female age range 2 months-16 years) presenting with complex symptoms potentially referable to large airways. INTERVENTION Flexible bronchoscopy for diagnostic (bronchoalveolar lavage, ciliary biopsy, assess ongoing surgical intervention, and rule in or rule out foreign body; N=6) or therapeutic (evacuate bronchial mucus plug, laser subglottis when patient has fused cervical spine, and distal instillation [fibrin glue for bronchopleural fistula and dornase alpha for plastic bronchitis]; N=4). MAIN OUTCOME MEASURE Retrospectively ask if flexible bronchoscopy and interdisciplinary management improved patient care in these select otolaryngology cases. RESULTS 10/10 patients benefited from interdisciplinary management including flexible bronchoscopy. CONCLUSION Our experience illustrates many uses for flexible bronchoscopy in otolaryngology patients, and suggests that an airway team prepared to use flexible bronchoscopy will create opportunities for improved patient care.